It is unknown why patients with type II insulin resistant (IR) diabetes mellitus have an increased incidence of atherosclerosis when compared to non-diabetics. Our goal is to develop porcine models of IR and a mixed model of IR plus familial hypercholesterolemia that will be useful in studies to define the role of IR in atherosclerosis. The pigs will be used to determine if the presence of IR causes an increased burden of atherosclerosis compared to control animals without IR and to determine if markers of atherosclerosis that are present in these animals will correlate with disease progression in IR animals. Two unique strains of pigs will be used, one from Chapel Hill (CH) with increased total body fat and a second with familial hypercholesterolemia (FH) that are lean. Both the CH and FH strains have subpopulations with and without increased insulin resistance (IR). In Aim I, CH-IR and FH-IR pigs will be bred for increased severity of IR. In Aim II, the effect of IR on the extent of coronary, aortic, and carotid artery atherosclerosis and the changes in serum and tissue markers of atherosclerosis will be determined in CH-IR pigs and compared to CH pigs without IR, both groups being fed a high fat atherogenic diet. A second study will compare these same variables in FH-IR and FH-nonIR pigs fed normal (low fat) pig chow. Intravascular ultrasound (IVUS) will be used during the study to monitor disease progression in vivo. Both IVUS and morphometry of fixed vessels will be used to measure atherosclerosis at termination. In Aim III, insulin like growth factor-I (IGF-1) will be given to the CH-IR pigs to reduce IR, and the pigs will be fed a high fat atherogenic diet. The extent of atherosclerosis and the changes in markers in these IGF-I treated pigs will be compared to controls. In Aim IV, the FH-IR pigs will be fed normal (low fat) pig chow and an aVb3 inhibitor that we have shown reduces atherosclerosis in non-IR pigs and its effect on lesion development determined. Our overall objective is to develop a useful, relevant, available model of IR and atherosclerosis that can be used to identify mechanisms that lead to accelerated atherosclerosis in insulin resistant humans and to develop and test potential new treatment strategies.